ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE

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Channels & disorders
 
Anions
 
ATPase
 
Calcium
 
Chloride
 
Concepts
 
Cyclic nucleotide-gated
 
Gap junctions
 
Long QT Syndromes
 
Magnesium
 
Mitochondrial solute carriers
 
Na+, K+, Cl- Co-transporters
 
Potassium
   
HCN
   
KCN
   
K+/H+ ATPase
 
Proton-gated
 
Sodium
   
Na+/H+ exchangers
   
Non-voltage-gated
   
Voltage-gated
 
Toxins
 
Transient receptor potential

Channel binding proteins

Transmitters/Receptors
 
Acetylcholine
 
ATP
 
Capsaicin
  Catecholamines
 
Dopamine
 
Glutamine
 
Glycine
 
Purines

Diagrams

CHANNEL TYPES: General9

  • Extracellular ligand-gated channels: Nicotinoid
    • 5 Homologous polypeptide subunits
    • Subunits have 4 membrane spanning regions
    • Ligands: Neurotransmitters
    • Specific receptors
      • Nicotinic AChR
      • GABAA & GABAC
      • Glycine
      • 5-HT3
      • Glutamate activated anionic channels
        • Types: NMDA; AMPA; Kainate
        • 4 Homologous subunits
  • Intracellular ligand-gated channels
    • Ligands: cAMP, cGMP, Ca++, G-proteins, Phosphorylation
  • Voltage-gated channels
    • 4 domains
      • Na+ & Ca+ channels: In single polypeptide chain
      • K+ channel: Tetramer of 4 similar subunits
    • Each domain has 6 membrane spanning regions
    • S4 sequence
      • Contains + charged amino acids (lysine and/or arginine)
      • "Senses" voltage across membrane: Regulates pore opening
    • Selective channel pore (Bacterial K+ channel model)
      • Dimensions: 12 long; 3 wide
      • Lined by main chain oxygen atoms
    • Ion selectivity: Na+, Ca++ or K+
  • Inward rectifier
    • P domain: "Selectivity filter"
    • 2 Flanking transmembrane region
    • Homo- or heterooligomers in membrane
    • Ion selectivity: K+
  • Gap junction channels
    • 6 polypeptide subunits
    • Each subunit has 4 membrane spanning regions
  • ATP gated channels: 3 Homologous polypeptide subunits

 


CHLORIDE CHANNELS

Principles
Disorders


Chloride channels: Principles14

Chloride channels: Disorders


SODIUM CHANNELS

Figure
Principles: Na+ channels
 
Exchangers
 
Non-voltage-gated
 
Voltage-gated
Na+ channel disorders


Sodium channels: Principles

 

Sodium channels: Disorders


CALCIUM CHANNELS

Ca++ channel disorders
Ca++ channel: Figures
Types
  Voltage-gated Ca++ channels
    Classes
    Principles
  Ca++ sensors
  Intracellular activation: Ryanodine +
  Ligand gated
  Other Ca++ channels


 
l Voltage-gated Ca++ entry channels: Principles

  l Other Ca++ channels

  l Ca++ sensors

  l Ca++ channel disorders


POTASSIUM CHANNELS

Figure
K+ channel disorders
Principles
  Structure
  Functions
  Subunits
Types


l Principles & Types of K+ Channels

 





 

 

 

 

 


 

l Disorders of K+ Channels

 


HYPOMAGNESEMIA


ANION CHANNELS, EXCHANGERS & TRANSPORTERS


CATION CHANNELS: CYCLIC NUCLEOTIDE-GATED

 


PROTON-GATED ION CHANNELS: Neural

 


 

Na-K-Cl CO-TRANSPORTERS (Solute carrier family (SLC) 12)

 


Stretch-activated non-selective cation channels (SA channels)

 


TRANSIENT RECEPTOR POTENTIAL (TRP) ION CHANNELS

General Features

TRP families12

 


GAP JUNCTIONS23

Gap junction


ION CHANNEL-BINDING PROTEINS: INTRACELLULAR

Ion channel

Binding protein

Mechanism & Effect

K+ channel, Voltage-gated
  Shaker type


NMDA receptor
  NR2 subunit

Chapsyns*: PSD-95 ;
SAP97 ; Chapsyn-110 ;
Sap102 ; Dlg

Binding via PDZ** domains
  1st & 2nd on PSD-95
Post-synaptic densities in CNS

NMDA receptor
  NR1 subunit

α-actinin

Actin binding protein
Concentrated in dendritic spines

Glycine receptor (GlyR)

Gephyrin

Binds to β intracellular loop
  of GlyR & tubulin

AChR: Nicotinic

Rapsyn/43K

Neuromuscular junction localization

Na+ channel
  Voltage-gated

Ankyrin G

Node of Ranvier localization

AMPA receptor
GluR2 subunit

Glutamate receptor
interacting protein (GRIP)

Binding via PDZ domain
Couples receptor to cytoskeletal
  & signaling molecules

Glutamate receptor
Metabotropic
Subunits: mGluR1a
  & mGluR5

Homer

Binding via PDZ-like domain
Expression
by synaptic activity

* Belong to Membrane Associated Guanylate Kinase (MAGUK) family
    Chapsyn = Channel associated protein of synapse
** PDZ domains: Homologous 90 amino acid sequence repeats; Bind other proteins


ACETYLCHOLINE RECEPTORS: Disorders


GLYCINE RECEPTORS

 

l β subunit ; Chromosome 4q31.3; Sporadic or Recessive

 

 


GLUTAMATE RECEPTORS


DOPAMINE RECEPTORS

 


Long QT Syndromes16

l KCNQ1 (KCNA8; KVLQT1) ; Chromosome 11p15.5; Recessive




Concepts in channelopathies

What are the properties of the mutations in the chloride channel gene (CLC1) that determine whether a syndrome is inherited in a dominant or recessive pattern?

The dominant or recessive
nature of a mutation depends on the ability of the mutant chloride channel monomers to polymerize with normal channel monomers. Dominant mutations complex with normal monomers producing defective channels. For some mutations one abnormal monomer is sufficient to destroy the function of a tetramer complex (e.g. Pro480Leu). For other mutations (e.g. Gly230Glu) it requires two abnomal monomers to destroy the channel function of a tetramer. In either case, only a minority of tetramers remain functional and myotonia results. Recessive mutations do not complex with normal monomers. Normal monomers are then free to complex with other normal monomers. This produces enough functional tetramers in heterozygotes (50% of the usual amount) to preserve normal membrane excitablity and myotonia does not occur.



What are the properties of the mutations in the sodium channel gene (SCN4A) that determine whether a syndrome presents with myotonia, paramyotonia, or weakness?

Many mutations produce abnormal inactivation of the sodium channel. This results in increased sodium conductance and membrane depolarization. Mild depolarization is associated with increased membrane excitability and myotonia. Strong depolarization produces membrane inexcitability and weakness. Some mutations only reduce inactivation at low temperatures producing paramyotonic disorders (myotonia or weakness worse in the cold). Mutations in the inactivation gate (amino acid 1306) produce different degrees of disease severity depending on the size and charge of the side chain of the new amino acid. Alanine, with a short side chain produces mild myotonia fluctuans. Valine, with an intermediate side chain, produces paramyotonia congenita. Glutamic acid, with a long side chain and a negative charge, results in myotonia permanens.


CHANNEL TOXINS

Marine toxins
  Ciguatoxin
  Conotoxins
  Palytoxin (Clupeotoxism)
  Tetrodotoxin
  Shell fish
    Saxitoxin: Paralytic
    Domoic acid: Encephalopathic
    Brevetoxins: Neurotoxic
    Diarrheic
Other
  Lidocaine
  Potassium channel

 


Marine toxins: General24


Ciguatera toxins7,8,11

Epidemiology
Toxicity
Clinical
Laboratory


Clupeotoxism


From NCI

Palytoxin


Conotoxins


Lidocaine


Saxitoxin


Tetrodotoxin

tetrodotoxin

Tetrodotoxin


Brevetoxins


From FDA


Domoic Acid


Diarrheic shellfish poisoning (DSP)



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References
1. TINS Supplement: June 1996
2. Toxin illustrations from Ion Channel Research
3.
Neurology 1997;49:1196-1199br> 4. Curr Opin Neurobiol 1999;9:267-273
5.
Trends in Neurosciences 1999;22:488-495
6.
Am J Hum Genet 2000;66 (May)
7.
Medical Jourmal of Australia 2000;172:176-179
8.
Medical Jourmal of Australia 2000;172:160-162
9.
Physiol Rev 2000;79:1317-1372; Clin Neurophysiol 2001;112:2-18
10.
TINS 2000;23:393-398, Arch Neurol 2003;60:496-500
11.
Muscle Nerve 2000;23:1598-1603; JNNP 2001;70:4-8
12.
Nature Reviews:Neuroscience 2001;2:387-396
13.
Arch Neurol 2001;58:1649-1653
14.
Physiol Rev 2002;82:503-568
15.
Nature 2002;417;501-502
16.
Ann Intern Med 2002;137:981-992
17.
Nature Neuroscience 2003;6;468-475
18.
Physiological Reviews 2003;83:117-161
19.
Ann Neurol 2003;54:239-243
20. Nature 2004;430:232-235
21. Hum Mol Genet 2004;13:17031714
22. Molec Neurobiol 2004;30:279-305
23. Molec Neurobiol 2004;30:341-357
24. Lancet Neurology 2005;4:219-228
25. Current Pharmaceutical Design 2005;11:1915-1940
26. J Neurosci 2007;27:11412-11415

6/19/2007